Enormous progress has been made to treat cancer, and yet the mortality rate of cancer remains unacceptably high. High clinical resistance to molecularly targeted therapeutics has pushed interest again towards inhibiting universal biochemical hallmarks of cancer. Recent evidence suggests that malignant tumors acidify the local extracellular environment to activate proteases for degrading the tumor matrix, which facilitates metastasis, and explains why more aggressive tumors are more acidic. Current therapies have only focused on using the low pH for enhancing drug release in tumors, thereby still relying on the traditional paradigm of intracellular inhibition of pathways, a method that continues to have mixed results. Thus, the goal of this proposal is to better eradicate cancer by developing a synergistic bifunctional nanoparticle platform that can both modulate the acidic extracellular environment (pHe) and deliver intracellular therapeutics. We propose: (Aim 1) Local long term neutralization of tumor pHe will inhibit tumor growth. Acid-neutralizing nanoparticles will be anchored to the local extracellular microenvironment by being covalently attached to a polypeptide that inserts into tumor plasma membranes under acidic conditions. pH change and treatment response in murine tumor models will be assessed by fluorescent pH probes. (Aim 2) Intracellular drug action combined with longitudinal neutralization of pHe of tumors will be synergistic. Doxorubicin will be linked to the internalizing segment of the nanoparticle-labeled peptide anchor. This dual acting therapy will be compared to traditional intracellular treatment in terms of tumor cells in vitro and in vivo treatment response. This research will develop a novel platform that can be made to monitor and modify the critical tumor extracellular environment as well as retain the ability for synergistic intracellular drug delivery Thus, this platform will be able to shift the paradigm of current cancer therapy from a solely intracellular approach to a dual (extracellular + intracellular) synergistic method of targeting cancer. By specifically neutralizing the tumor extracellular microenvironment, the proposed platform aims to prevent tumor progression and metastasis as well as minimize the traditional intracellular based pathways of resistance. Because of the broad universal aspect of low extracellular pH in cancer, particularly in the more malignant tumors, this platform will have also wide applicability, with particular potency on the most aggressive of cancers.